Dopamine is an important neurotransmitter, important in regulation of human neurological and psychiatric health. Loss of dopaminergic neurons in the substantia nigra pars compacta, located in the brainstem, is responsible for Parkinson's disease, a debilitating neurological disorder of the aged, see O. Horniykiewicz, Fed. Proc., 32:183 (1973). Parkinson's disease is characterized by akinesia (difficulty of initiation of movement) and resting tremor. Because of these properties, it is also referred to as paralysis agitans. This condition is treatable with dopamine agonists. However, because such agonists tend to stimulate dopamine systems too strongly, they induce dyskinesia (excessive abnormal involuntary movements), see T. N. Chase et al., Arch. Neurol. 30:383 (1974).
Dopaminergic dysregulation is also the likely etiology for schizophrenia, perhaps the most serious of all psychiatric disorders see A. Randrup and I. Mukvad, Psychopharmacol. 11:300 (1967) and S. H. S. H. Snyder et al., Science, 184:1234 (1974). Schizophrenia is characterized by clusters of positive and negative symptoms that vary among patients. Positive symptoms include hallucinations, paranoia, feelings of grandiosity, disconnectedness of thought, and a general dissociation from reality. Negative symptoms include withdrawal, flattened affect, and loss of communication. Positive symptoms of schizophrenia are due to excessive activities in dopaminergic neuronal systems. These symptoms are treated with dopamine receptor antagonists, see C. A. Tamminga and J. Gerhlach, "In Psychopharmacology: The Third Generation of Progress", H. Meltzer (ed.), Raven Press, N.Y., 1987, p. 1129. Unfortunately, because such antagonists completely shut off the dopamine system, they induce a variety of symptoms, generally referred to as extrapyramidal symptoms (EPS), which are essentially indistinguishable from natural Parkinsonism, see C. A. Tamminga and J. Gerhlach, "In Psychopharmacology: The Third Generation of Progress", H. Meltzer (ed.), Raven Press, N.Y., 1987, p. 1129. Thus, schizophrenic patients are asked to trade a psychiatric condition for a neurological one. Moreover, dopamine antagonists are generally unable to ameliorate negative symptoms of schizophrenia, probably because these symptoms result from a depression in dopaminergic activity, see R. J. Wyatt, Research in the Schizophrenic Disorders: The Stanley R. Dean Award Lectures", vol. 2, R. Cancro and S. R. Dean (eds), Spectrum Publ., 1985, p. 225.
A different approach to treating diseases of dopaminergic dysregulation is through dopamine partial agonists. Such agents are dopamine agonists but their maximal effects are weaker than full dopamine agonists such as apomorphine and dopamine itself. Such agents will act as agonists in systems having little or no dopaminergic activity, and as antagonists when dopaminergic activity is high. Thus, such agents could treat both positive and negative symptoms of schizophernia, as well as Parkinson's disease. The concept of partial agonists is not specific to dopaminergic systems, and the theoretical basis for the concept is discussed in detail elsewhere see E. J. Ariens, Molecular Pharmacology, vol. 1, Academic Press, N.Y., pp. 503 (1964). Partial agonist activity is defined by the level of intrinsic activity. Intrinsic activities are defined as the maximal effect of a drug expressed as a fraction of the maximal effects of the most effective agonists. Dopamine antagonists have intrinsic activities of zero. That is, they have no agonist effects, but they bind to dopamine receptors, thus blocking access of dopamine and other dopamine agonists to activate the receptors. On the other hand, Full dopamine agonists have intrinsic activities of one; at their highest concentrations they stimulate dopaminergic systems to express their maximal possible outputs. Partial agonists have intrinsic activities between zero and one. Partial agonists by themselves will stimulate dopaminergic systems, but even at their highest dosage they cannot stimulate these systems to produce their maximal possible outputs. Since at their highest doses they will fully saturate the receptor sites, they block access of full agonists (e.g. dopamine) and, therefore, act as antagonists.
Since the full expression of biological activity is equal to the product of the percentage of receptors occupied times the intrinsic activity of the occupying drug, one should be able to "clamp" dopaminergic systems in a normal range by saturating the receptors with a drug having an intrinsic activity near the normal fraction of receptors occupied by dopamine, the natural mediator. Since the fraction of receptors normally occupied is not known, the ideal intrinsic activity for a partial agonist is also not known. This is accentuated by the fact that few dopamine partial agonists are known. The current invention describes certain phenylureas of sufficiently low intrinsic activity to be useful as partial dopamine agonists for the treatment of disease conditions resulting from or worsened by dysregulation of dopaminergic systems. Such conditions include schizophrenia and Parkinsonism, and may also include such diseases as drug addiction, attention deficit disorders (ADD), Tourrette's syndrome, autism, appetite control, hyperprolactinemia and other endocrine disorders, sexual dysfunction, and cardiovascular disorders such as hypertension and congestive heart failure.